7.7 Preserved EF (HFpEF)

7.7.1 HF With Preserved Ejection Fraction

Synopsis

HFpEF (LVEF ≥50%) is highly prevalent, accounting for up to 50% of all patients with HF, and is associated with significant morbidity and mortality (14). HFpEF is a heterogenous disorder, contributed to by comorbidities that include hypertension, diabetes, obesity, CAD, CKD, and specific causes such as cardiac amyloidosis (15-17). Clinical trials have used variable definitions of HFpEF (e.g., LVEF ≥40%, 45%, or 50%, and the varying need for accompanying evidence of structural heart disease or elevated levels of natriuretic peptides) (18). Until recently, clinical trials had been generally disappointing, with no benefit on mortality and marginal benefits on HF hospitalizations (5,8,11,19,20). Currently, recommended management is that used for HF in general with use of diuretics to reduce congestion and improve symptoms (see Section 7.1.1 for recommendations for nonpharmacological management and Section 7.2 for recommendations for diuretics), identification and treatment of specific causes such as amyloidosis, and management of contributing comorbidities such as hypertension, CAD, and AF (see Section 10.2 for recommendations on management of AF). Figure 12 summarizes COR 1, 2a, and 2b for HFpEF.

Recommendation-Specific Supportive Text

1. The role of blood pressure control is well established for the prevention of HF, as well as for reduction of other cardiovascular events and HF mortality in patients without prevalent baseline HF (1-3,21-24). The SPRINT (Systolic Blood Pressure Intervention) trial and meta-analyses established that more intensive blood pressure control in patients with high cardiovascular risk significantly reduces HF and other cardiovascular outcomes (2,3,25). In recent clinical practice guidelines for hypertension, blood pressure targets in HFpEF are extrapolated from those for treatment of patients with hypertension in general (26). However, the optimal blood pressure goal and antihypertensive regimens are not known for patients with HFpEF. RAAS antagonists including ACEi, ARB, MRA, and possibly ARNi, could be first-line agents given experience with their use in HFpEF trials (8,10,16,20,27,28). Beta blockers may be used to treat hypertension in patients with a history of MI (27), symptomatic CAD, or AF with rapid ventricular response. These effects need to be balanced with the potential contribution of chronotropic incompetence to exercise intolerance in some patients (29).

2. EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) showed a significant benefit of the SGLT2i, empagliflozin, in symptomatic patients with HF with LVEF >40% and elevated natriuretic peptides (30). The 21% reduction in the primary composite endpoint of time to HF hospitalization or cardiovascular death was driven mostly by a significant 29% reduction in time to HF hospitalization (nonsignificant lower cardiovascular death [HR, 0.91; 95% CI, 0.76-1.0]), with no benefit on all-cause mortality. Empagliflozin also resulted in a significant reduction in total HF hospitalizations, decrease in the slope of the eGFR decline, and a modest improvement in QOL at 52 weeks. Of note, the benefit was similar irrespective of the presence or absence of diabetes at baseline. Although the benefit in the primary endpoint did not have a significant interaction by LVEF subgroups (<50%, 50%–<60%, and >60%) (30), in a subgroup analysis by EF, there was a signal for lower benefit on the primary composite endpoint, first and recurrent HF hospitalizations at higher LVEFs >62.5% (31).

3. Large, randomized clinical trial data are unavailable to specifically guide therapy in patients with HFpEF and AF. Currently, the comprehensive care of AF can be extrapolated from the clinical practice guidelines for AF, with individualization of strategies for rate or rhythm control in patients with HFpEF (see also Section 10.2, “Management of Atrial Fibrillation (AF) in HF,” for HF specific recommendations for AF). Although beta blockers and nondihydropyridine calcium channel blockers are often considered as first-line agents for heart rate control in patients with HFpEF, a recent smaller open-label trial, RATE-AF in elderly patients with AF and symptoms of HF (most with preserved LVEF), compared the use of the beta blocker, bisoprolol, to digoxin (32). At 6 months, the primary endpoint of QOL was similar between the 2 groups. However, several secondary QOL endpoints, functional capacity, and reduction in NT-proBNP favored digoxin at 12 months. There was a similar heart rate reduction in both groups. Of note, more adverse events such as higher rates of dizziness, lethargy, and hypotension occurred with beta blockers than digoxin. The comprehensive care of AF is beyond the scope of these guidelines. AF-specific care recommendations can be found in separate ACC/AHA clinical practice guidelines (33,34).

4. MRAs improve diastolic function in patients with HFpEF (35). The TOPCAT trial investigated the effects of spironolactone in patients with HFpEF. The small reduction (HR, 0.89) in the composite of death, aborted cardiac death, and HF hospitalization was not statistically significant, although HF hospitalization was reduced (HR, 0.83); adverse effects of hyperkalemia and increasing creatinine levels were more common in the treatment group (5). A post hoc analysis (6) showed efficacy in the Americas (HR 0.83) but not in Russia-Georgia (HR 1.10). A sample of the Russia-Georgia population in the active treatment arm had nondetectable levels of a spironolactone metabolite. Post hoc analyses have limitations, but they suggest a possibility of benefit in appropriately selected patients with symptomatic HFpEF (LVEF ≥45%, elevated BNP level or HF admission within 1 year, eGFR >30 mL/min/1.73 m², creatinine <2.5 mg/dL, and potassium <5.0 mEq/L). Furthermore, another post hoc analysis suggested that the potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum (7). Careful monitoring of potassium, renal function, and diuretic dosing at initiation and follow-up are key to minimizing the risk of hyperkalemia and worsening renal function.

5. Although RAAS inhibition strategies have been successful in the treatment of HFrEF, and RAAS activation is suggested in HFpEF (36,37), clinical trials with RAAS inhibition have not showed much benefit in patients HFpEF. In the CHARM-Preserved (Candesartan in patients with chronic HF and preserved left-ventricular ejection fraction) trial, patients with LVEF >40% were randomized to an ARB, candesartan, or to placebo (38). The primary endpoint (cardiovascular death or HF hospitalization) was not significantly different between the 2 groups (HR, 0.89; 95% CI, 0.77–1.03, P=0.118; covariate-adjusted HR, 0.86; P=0.051). Cardiovascular mortality was identical in the 2 groups; HF hospitalizations were lower in the candesartan arm, with borderline statistical significance on the covariate-adjusted analysis only (HR, 0.84; 95% CI, 0.70–1.00; P=0.047; unadjusted P=0.072). The number of individuals hospitalized for HF (reported by the investigator) was lower in the candesartan group than placebo (230 versus 279; P=0.017). A post hoc analysis of the CHARM trials showed that improvement in outcomes with candesartan was greater at the lower end the LVEF spectrum (39). In a meta-analysis of 7694 patients with HFpEF in 4 trials evaluating ARB, there was no signal for benefit on cardiovascular mortality (HR, 1.02), all-cause mortality (HR, 1.02), or HF hospitalization (HR, 0.92; 95% CI, 0.83–1.02) (40,41).

6. In the PARAMOUNT-HF (Prospective Comparison of ARNi With ARB on Management of Heart Failure With Preserved Ejection Fraction) trial, a phase II RCT in patients with HFpEF (LVEF ≥45%), sacubitril-valsartan resulted in a lower level of NT-proBNP after 12 weeks of treatment compared with the ARB, valsartan (42). In the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, in 4822 patients with HFpEF (LVEF ≥45%, HF admission within 9 months or elevated natriuretic peptide levels, and eGFR ≥30 mL/min/m²), sacubitril-valsartan compared with valsartan did not achieve a significant reduction in the primary composite endpoint of cardiovascular death or total (first and recurrent) HF hospitalizations (rate ratio, 0.87; 95% CI, 0.75-1.01; P=0.06) (10). Given the primary outcome was not met, other analyses are exploratory. There was no benefit of sacubitril-valsartan on cardiovascular death (HR, 0.95) or total mortality (HR, 0.97). There was a signal of benefit for the ARNi for HF hospitalizations (rate ratio, 0.85; 95% CI, 0.72–1.00; P=0.056). The occurrence of hyperkalemia and the composite outcome of decline in renal function favored sacubitril-valsartan, but it was associated with a higher incidence of hypotension and angioedema. In prespecified subgroup analyses, a differential effect by LVEF and sex was noted. A benefit of sacubitril-valsartan compared with valsartan was observed in patients with LVEF below the median (45%–57%; rate ratio, 0.78; 95% CI, 0.64–0.95), and in women (rate ratio, 0.73; 95% CI, 0.59–0.90) (10,43,44).

7. Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with HFrEF. However, the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial (45) randomized 110 patients with EF ≥50% on stable HF therapy, not including nitrates, and with activity limited by dyspnea, fatigue, or chest pain, to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels, QOL, exercise tolerance, or NT-proBNP levels. Although the routine use of nitrates in patients with HFpEF does not appear beneficial, patients with HFpEF and symptomatic CAD may still receive symptomatic relief with nitrates. Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity. The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial (13) randomized 216 patients with EF ≥50% on stable HF therapy and with reduced exercise tolerance (peak observed VO₂, <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo. This study did not show improvement in oxygen consumption or exercise tolerance.